Mental disorders refer to varying degrees of disorders in mental activities including cognition, emotion, behavior and volition caused by brain dysfunction. Common mental disorders include schizophrenia, depression, manic depressive disorder (bipolar disorder), anxiety disorder, phobia, obsessive-compulsive disorder, stress-related disorder, mental disorder associated with organic lesion, etc. Statistically, mental disorders account for more than 15% of the global burden of disease. Mental diseases rank first, with a percentage of 20%, in the total burden of disease in China. It is reported that the incidence of mental diseases in China is as high as 17.5%, wherein severe mental disorders is up to 1%.
Monoamine and receptors thereof are one of the most widely studied neurotransmitters and receptors on pathogenesis in psychiatry research. The pathogenesis of schizophrenia mainly include dopamine (DA) hyperactivity hypothesis, and hypothesis concerning the neural pathway blockage of 5-hydroxytryptamine (5-HT) and norepinephrine (NE). Studies show that positive symptoms (such as hallucination, delusion, etc.) in the schizophrenics may be associated with DA hyperfunction in subcortical limbic system. Antipsychotic drugs, which exert a pharmacological action by blocking Dopamine D2 Receptor (DRD2), can effectively control positive symptoms of schizophrenia.
Glutamate and aspartate are the most common excitatory neurotransmitters in central nervous system. Studies suggest that abnormal glutamatergic transmission is involved in schizophrenia and other mental disorders. N-methyl-D-aspartic acid (NMDA) receptor antagonists can induce schizophrenia-like effects; and substances, which enhance NMDA receptor function, can improve symptoms and cognitive functions in the schizophrenics.
More and more evidences have shown that inflammation and immune dysfunction may be closely associated with the development and progression of schizophrenia, depression, and other mental disorders. In the brains of patients with schizophrenia and patients at high risk for schizophrenia, immune cells (microglial cells) are more active, indicating that neuroinflammatory response is an important factor in schizophrenia, and has become a new potential target for the treatment and prevention of schizophrenia. In addition, it is shown that, in human autopsy studies and special imaging techniques, as well as studies on animal depression models, depression may occur when microglial cells change and fail to modulate brain function and behavioral progress any more. Long-term exposure to chronic, unpredictable psychological stress can also lead to changes in the shape and function of microglial cells, and such a stress is also one of the most important causes for depression in human.
Plenty of studies indicate that microglial activation and neuroinflammation are the important pathogenesis for nervous system diseases such as neurodegenerative disease (e.g. Alzheimer's disease, Parkinson's disease), cerebrovascular disease, brain trauma, spinal cord injury, demyelinating disease, multiple sclerosis, and encephalomyelitis.
White matter, which is an important component of central nervous system, is also the place where nerve fibers accumulate. Damage of myelin sheath in central nerve cells can result in pathological changes in white matter. In patients with schizophrenia, depression and other mental disorders, as well as patients with cerebrovascular disease, diabetic neuropathy, etc., nerve fibers in white matter are abnormal, such as changes in myelin sheath, and disordered axons; and demyelinating diseases such as multiple sclerosis may have the symptoms of mental disorder. These results indicate that pathological changes in white matter are closely associated with the pathogenesis of mental disorders and some nervous system diseases.
At present, antipsychotic drugs applied in clinic can be divided into two classes: one is the first-generation antipsychotic drugs that can block dopamine receptors, known as “classical” antipsychotic drugs (such as haloperidol, etc.). Although they can effectively control the positive symptoms of schizophrenia, they have little therapeutic effect on cognitive disorder. The other one is the drugs that act on both dopamine receptor and other receptors (such as serotonin receptor, norepinephrine receptor), known as “non-classical” antipsychotic drugs (such as ziprasidone, risperidone, etc.). Although these drugs have certain therapeutic effects both on the positive symptoms and negative symptoms of schizophrenia, similarly, they have litter therapeutic effect on cognitive disorder.
To sum up, there are still no antipsychotic drugs that can improve cognitive disorder. In addition, there are not sufficient studies on these drugs that can simultaneously act on multiple targets involved in the complex pathogenesis of a mental disorder and a neurological disease, such as dopaminergic system, glutamatergic system, microglial cells and white matter.
Therefore, it is of important significance in clinical treatment to develop drugs against mental disorders and neurological diseases, which act on multiple targets.